Rizatriptan is an orally active serotonin 5-HT1 receptor agonist selective for the 5-HT1b/1dsubtypes.
The efficacy of oral rizatriptan (5 or 10mg) has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan.
Two hours postdose, rizatriptan 5 or 10mg was more effective than placebo at producing pain relief or a pain free status, relieving migraine-associated symptoms and normalising functional ability. In general, rizatriptan 10mg appeared to be more effective than rizatriptan 5mg. However, recurrence rates with rizatriptan 5 and 10mg appeared to be similar to those with placebo.
Patients were significantly more likely to achieve pain relief within 2 hours after receiving rizatriptan 5mg than sumatriptan 25mg and after rizatriptan 10mg than sumatriptan 50mg. This was also observed with rizatriptan 10mg compared with sumatriptan 100mg according to an age-adjusted and a prespecified per-protocol analysis. In general, rizatriptan was better than sumatriptan at relieving migraine-associated symptoms, particularly nausea, and in normalising functional ability depending on which doses were compared. The incidence of headache recurrence, time to onset of recurrence and the need for escape medication in nonresponders appeared to be similar between rizatriptan and sumatriptan.
Over the 24 hours after the dose, rizatriptan 10mg improved the quality of life of patients with migraine compared with placebo. Rizatriptan 10mg also significantly improved work function compared with placebo and with sumatriptan 50mg.
Rizatriptan appears to be well tolerated with most adverse events being mild and transient. The most commonly experienced events included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/ fatigue and pain and pressure sensations. In clinical trials, the overall incidence of adverse events with rizatriptan 5 or 10mg was similar to that with sumatriptan 25 or 50mg but lower than that with sumatriptan lOOmg. Chest pain was reported by 1 to 3% of rizatriptan recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or lOOmg); clinically significant effects on ECG parameters, heart rate or blood pressure were not observed with rizatriptan.
Conclusions: Rizatriptan produces pain relief and a pain free status, relieves associated symptoms of migraine, normalises functional ability and improves patient quality of life. Rizatriptan 10mg appears to be more effective than rizatriptan 5mg. In comparison with oral sumatriptan, rizatriptan may provide better relief from pain and nausea, with some evidence of a faster onset of action. Thus, rizatriptan 5 or 10mg is likely to establish a place as an effective and well tolerated agent for the management of acute migraine.
Rizatriptan is an orally active serotonin 5-HT1 receptor agonist which selectively acts at the 5-HT1b/1d subtypes.
In vitro, at supra-therapeutic doses, rizatriptan produced greater maximum contraction of human cranial arteries and less vasoconstriction of human coronary arteries than sumatriptan.
Rizatriptan inhibited electrically-induced, but not neuropeptide-induced, vasodilation of the durai blood vessels in rats, possibly by reducing neuropeptide release. Durai plasma protein extravasation was also inhibited by rizatriptan and this action may contribute to the drug’s antimigraine effect. Rizatriptan inhibited electrically-induced firing of neurons from the trigeminal nucleus caudalis in rats, suggesting a central antinociceptive effect.
In small studies in healthy volunteers or patients with controlled hypertension, rizatriptan (0.5 to 80mg as a single dose or 10mg every 2 hours for 3 doses per day for 4 days) generally produced only small, transient increases in blood pressure and did not alter heart rate, or affect the increases in blood pressure and heart rate in response to sympathetic stimulation. However, it is important to note that, as with other 5-HT1b/1d agonists, rizatriptan is contraindicated in patients with coronary artery disease or uncontrolled hypertension.
In a small study in healthy volunteers, no additive effects on systolic blood pressure were observed when rizatriptan 10mg was added to intravenous ergot-amine 0.25mg.
Oral rizatriptan in single doses of 20 to 60mg produced a transient increase in growth hormone levels similar to that after sumatriptan 100mg, but had no effect on prolactin levels.
Oral Administration: After single dose oral rizatriptan 5 to 60mg in healthy male volunteers, the maximum plasma concentration (Cmax) ranged from 7.8 to 90.8 µg/L, the area under the plasma concentration-time curve (AUC) ranged from 17.4 to 394.5 µg/L · h. The mean time to achieve Cmax (tmax) was 0.7 to 2.1 hours after single dose rizatriptan 2.5 to 60mg. The median tmax of rizatriptan (5 to 60mg) was significantly lower than the tmax of oral sumatriptan 100mg (1.3 vs 2.5 hours). The elimination half-life (t½) of rizatriptan was about 2 to 2.5 hours. The main route of elimination of rizatriptan is metabolism via the monoamine oxidase A enzyme; the major indole-3-acetic acid metabolite is inactive at 5-HT1b/1d receptors but a minor N-monodesmethyl metabolite has similar activity to the parent drug.
The presence of food increased the extent and decreased the rate of rizatriptan absorption without altering t½ values. Multiple rizatriptan doses increased values for absorption (Cmax, tmaxand AUC) but not elimination (t½ and renal clearance) parameters, and there was no unexpected accumulation. Pharmacokinetic parameters (Cmax, AUC and t½) appear similar in adolescent migraineurs compared with healthy volunteers. It is unclear whether rizatriptan pharmacokinetics differ between men and women.
Intravenous Administration: In healthy volunteers, plasma clearance, volume of distribution at steady state, t½ and the mean retention time in the body were similar, and AUC increased dose-proportionally after intravenous rizatriptan 10 to 60 µg/kg or 0.5 to 2.5mg (estimated as 6.5 to 42 µg/kg). However, when the rizatriptan dose was increased from 60 to 90 µg/kg or from 2.5 to 5mg (from about 33 to 42µg/kg to about 65 to 85 µg/kg), plasma clearance and volume of distribution at steady state decreased. The increase in AUC was disproportional when the rizatriptan dose was increased from 60 to 90 µg/kg.
The efficacy of oral rizatriptan (5 or 10mg) [standard tablets and orally disintegrating tablets] has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan.
Rizatriptan 5 or 10mg (standard tablets) was more effective than placebo at producing pain relief or a pain free status. Pain relief at 2 hours after treatment of a single migraine attack was reported in about 59 to 77% of rizatriptan recipients compared with 26 to 40% of patients receiving placebo. Furthermore, 25 to 44% of rizatriptan recipients were pain free compared with 7 to 10% of placebo recipients. The significant effect on pain relief versus placebo was generally apparent from 1 hour after the dose, although in the largest trial rizatriptan (5 and 10mg) was more effective than placebo at 30 minutes after the dose. This increased effect compared with placebo was also observed at 30 minutes after a 10mg dose in the 1 trial using the orally disintegrating tablets. A similar trend in the incidence of these 2 pain parameters was observed between rizatriptan 10mg and placebo in subsequent migraine attacks. Rizatriptan also significantly reduced the need for rescue medication at 2 hours after the dose in nonresponders to the initial dose, improved functional disability and relieved migraine-associated symptoms compared with placebo.
The incidence of headache recurrence and the time to the onset of recurrence appeared to be similar between rizatriptan 5 and 10mg and placebo. After treatment of the first recurrence, significantly more patients reported pain relief after rizatriptan 10mg, and were pain free after rizatriptan 5 and 10mg, than after placebo.
In a trial in 105 patients with migraine associated with menses, significantly more patients receiving rizatriptan 10mg than placebo reported pain relief at 2 hours (75 vs 55%).
In a comparative trial with sumatriptan, rizatriptan 5mg recipients were significantly more likely to achieve earlier pain relief within the 2 hours after the dose (primary end-point) than patients receiving sumatriptan 25mg. Rizatriptan 10mg recipients were also significantly more likely to achieve pain relief within 2 hours than patients receiving sumatriptan 50mg, and when compared with sumatriptan 100mg recipients according to an age-adjusted analysis and a prespecified per-protocol analysis.
In patients experiencing migraine-associated symptoms at baseline, at 2 hours significantly greater relief of nausea was achieved with rizatriptan 5 and 10mg than with sumatriptan 25 and 50mg, respectively, and rizatriptan 10mg was significantly better than sumatriptan 100mg at relieving nausea, phonophobia and photophobia. At 2 hours, functional ability was normalised in significantly more patients receiving rizatriptan 10mg than in sumatriptan 100mg recipients, but no significant differences were observed between rizatriptan 5mg and sumatriptan 25 or 100mg or between rizatriptan 10mg and sumatriptan 50mg.
In general, the need for escape medication at 2 hours after the dose and the incidence of headache recurrence and time to onset of recurrence appeared to be similar between rizatriptan and sumatriptan.
When quality-of-life (QOL) parameters were assessed at 24 hours after the dose, rizatriptan 5 and 10mg significantly improved all QOL parameters in 1 trial, and improved work function in another study, compared with placebo. Rizatriptan 5 and 10mg improved patient quality of life to a similar extent to sumatriptan 25 and 50mg, respectively, except for the work domain in which rizatriptan 10mg was significantly better than sumatriptan 50mg.
In a large (n = 1746) long term (≤1 year) trial, the median number of attacks during which patients reported pain relief and were pain free was significantly greater with rizatriptan 10mg than with usual treatment (typically sumatriptan) [90 vs 70% and 50 vs 29%, respectively]. However, no significant differences were observed in these parameters between rizatriptan 5mg and usual treatment, and rizatriptan 10mg was significantly more effective than rizatriptan 5mg.
Rizatriptan (5 or 10mg) is generally well tolerated and adverse events are usually mild and transient. The incidence of events appears to be dose related and is similar after single and multiple doses. The overall incidence of adverse events appeared to be similar between rizatriptan (5 and 10mg) and sumatriptan (25 and 50mg) but significantly lower with both rizatriptan doses than with sumatriptan 100mg.
Most adverse events occurring more commonly with rizatriptan than with placebo were related to the gastrointestinal tract or the CNS. These included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/fatigue and pain and pressure sensations.
In clinical trials, individual events which were reported less frequently with rizatriptan (5 or 10mg) than with sumatriptan (50 or 100mg) included asthenia/ fatigue, nausea and headache. However, dry mouth was more common after rizatriptan 5mg than after sumatriptan 50mg, and dizziness occurred more frequently after rizatriptan (5 and 10mg) than after sumatriptan 25mg. These adverse events were, however, reported by relatively small percentages of patients (<10%) receiving either agent.
Chest pain was reported by 1 to 3% of rizatriptan (5 or 10mg) recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or 100mg) according to trial data. The incidence of this event was significantly greater with rizatriptan 5mg and sumatriptan 25 and 50mg than with placebo in 1 trial, but similar with rizatriptan 5 and 10mg and sumatriptan 100mg compared with placebo in another trial. In comparison with sumatriptan 100mg, the incidence of chest pain was significantly less frequent with rizatriptan 5mg but similar to that with rizatriptan 10mg. No clinically significant changes in blood pressure, heart rate, ECG parameters or laboratory parameters were observed after any agent.
The withdrawal rate from trials because of adverse events appeared to be higher with rizatriptan 5mg than with sumatriptan 25mg, similar between rizatriptan 10mg and sumatriptan 50mg and similar between both doses of rizatriptan and sumatriptan 100mg.
In the long term trial comparing rizatriptan 5 and 10mg with usual antimigraine treatment, the overall incidence of adverse events (causality not established) was similar between rizatriptan 10mg (80%) and usual treatment (78%) and both incidences were significantly higher than that with rizatriptan 5mg (68%). However, the incidence of each individual event appeared to be similar between both doses of rizatriptan and usual treatment.
Dosage and Administration
Rizatriptan is available as a standard tablet and as an orally disintegrating tablet. The orally disintegrating tablet dissolves rapidly on the tongue and may be useful for patients with swallowing difficulties or those without access to liquids during an attack.
The recommended dose of rizatriptan, from the prescribing information available in the US, is 5 or 10mg initially which can be repeated every 2 hours if necessary for recurrence to a total of 30mg in a 24-hour period. A dose reduction is generally not necessary in elderly patients.
The use of rizatriptan in children and nursing mothers has not yet been established, and use in pregnancy is only recommended after assessing the risk-benefit ratio.
Rizatriptan is contraindicated in patients with coronary artery disease or any other significant cardiovascular disease, uncontrolled hypertension, or hemiplegic or basilar migraine. It should be used with caution in patients reporting signs or symptoms suggestive of angina, patients on dialysis or in patients with moderately impaired hepatic function.
Drugs which may interact with rizatriptan or have additive effects include propranolol, monoamine oxidase inhibitors, ergotamine or ergot-containing drugs and other 5-HT1 receptor agonists. Observation of patients is advised if rizatriptan is coadministered with selective serotonin reuptake inhibitors.